Patients with Acquired Immune Deficiency Syndrome-related Dementia (AIDSD) exhibit a broad spectrum of motor impairments and cognitive deficits, which follow or parallel cellular loss, atrophy and morphological changes in their brains. The viral envelope glycoprotein gp120 has been suggested to be a causal agent of neuronal loss. However, little is known about the molecular and cellular mechanisms of this effect. The aim of the present study is to test the novel and challenging but timely hypothesis that gp120, released from microglia or astrocytes, causes apoptotic cell death by being internalized by neurons and retrogradely transported to neuronal cell bodies. We plan to test this hypothesis by using two strains of gp120, IIIB and BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively. Gp120 will be acutely injected into two well-established neuronal pathways of the rat brain, the nigrostriatal and septohippocampal pathways. In particular, we will inject gp120 into the caudate nucleus or fimbria and examine gp120 immunoreactivity in the substantia nigra and septal nuclei, respectively. These studies will be followed by analyses of cell types transporting gp120 by using antibodies against specific neuronal and non-neuronal markers. In addition, we will examine whether neurons positive for gp120 show signs of apoptosis by histologically measuring active caspase-3,-8 and -9. Moreover, we will investigate the hypothesis that gp120 may enter the central nervous system by axonal retrograde transport from peripheral nerves. The rat sciatic nerve will be exposed to gp120 and gp120 immunoreactivity will be determined in dorsal root ganglia and motor neurons of lumbar spinal cord. The retrograde transport hypothesis will be further tested by ligating the sciatic nerve to block axonal transport and examining gp120 accumulation. Overall, the results of the present study will provide a major break-through on the mechanisms whereby gp120 causes neuronal cell death and the related morphological alterations that may account for the motor and cognitive deficits found in AIDSD.